Martins V R, Mercadante A F, Cabral A L, Freitas A R, Castro R M
Centro de Tratamento e Pesquisa, Hospital do Câncer, Universidade de São Paulo, São Paulo, SP, Brasil.
Braz J Med Biol Res. 2001 May;34(5):585-95. doi: 10.1590/s0100-879x2001000500005.
Prions have been extensively studied since they represent a new class of infectious agents in which a protein, PrPsc (prion scrapie), appears to be the sole component of the infectious particle. They are responsible for transmissible spongiform encephalopathies, which affect both humans and animals. The mechanism of disease propagation is well understood and involves the interaction of PrPsc with its cellular isoform (PrPc) and subsequently abnormal structural conversion of the latter. PrPc is a glycoprotein anchored on the cell surface by a glycosylphosphatidylinositol moiety and expressed in most cell types but mainly in neurons. Prion diseases have been associated with the accumulation of the abnormally folded protein and its neurotoxic effects; however, it is not known if PrPc loss of function is an important component. New efforts are addressing this question and trying to characterize the physiological function of PrPc. At least four different mouse strains in which the PrP gene was ablated were generated and the results regarding their phenotype are controversial. Localization of PrPc on the cell membrane makes it a potential candidate for a ligand uptake, cell adhesion and recognition molecule or a membrane signaling molecule. Recent data have shown a potential role for PrPc in the metabolism of copper and moreover that this metal stimulates PrPc endocytosis. Our group has recently demonstrated that PrPc is a high affinity laminin ligand and that this interaction mediates neuronal cell adhesion and neurite extension and maintenance. Moreover, PrPc-caveolin-1 dependent coupling seems to trigger the tyrosine kinase Fyn activation. These data provide the first evidence for PrPc involvement in signal transduction.
自从朊病毒代表一类新型感染因子以来，人们对其进行了广泛研究。在这类感染因子中，一种蛋白质，即朊病毒瘙痒病蛋白（PrPsc），似乎是感染性颗粒的唯一成分。它们引发可传播性海绵状脑病，这种疾病会影响人类和动物。疾病传播机制已得到充分理解，涉及PrPsc与其细胞异构体（PrPc）的相互作用，以及随后后者的异常结构转变。PrPc是一种糖蛋白，通过糖基磷脂酰肌醇部分锚定在细胞表面，在大多数细胞类型中表达，但主要在神经元中表达。朊病毒疾病与异常折叠蛋白的积累及其神经毒性作用有关；然而，尚不清楚PrPc功能丧失是否是一个重要因素。新的研究正在解决这个问题，并试图阐明PrPc的生理功能。至少产生了四种PrP基因被敲除的不同小鼠品系，关于它们表型的结果存在争议。PrPc在细胞膜上的定位使其成为配体摄取、细胞黏附和识别分子或膜信号分子的潜在候选者。最近的数据表明PrPc在铜代谢中具有潜在作用，而且这种金属会刺激PrPc的内吞作用。我们的研究小组最近证明，PrPc是层粘连蛋白的高亲和力配体，这种相互作用介导神经元细胞黏附以及神经突的延伸和维持。此外，PrPc - 小窝蛋白 - 1依赖性偶联似乎会触发酪氨酸激酶Fyn的激活。这些数据为PrPc参与信号转导提供了首个证据。
